ABSTRACT Numerous retinal degenerative disorders are characterized by the loss of retinal ganglion cells (RGCs). As RGCs serve as the connection between the eye and the brain, the loss of these cells is often associated with a loss of vision. While neuroprotective strategies may help rescue vision at early stages of a disease, the subsequent loss of RGCs necessitates the development of strategies to functionally replaces those cells that have been lost. As the projection neurons of the visual system, however, efforts to replace RGCs have encountered numerous obstacles owing to their long-distance projections and need to establish precise synaptic contacts. As such, limited success has been achieved to date in efforts to either regenerate endogenous RGCs or to replace these cells with stem cell-derived RGCs. Although previous approaches to replace RGCs have largely focused upon the use of rodent models, numerous differences exist between rodent and primate retinas. Notably, the number and types of RGCs present within the retinas of the two species vary, with rodents having approximately twice the diversity of RGC subtypes. Importantly, these subtypes have been shown to exhibit differential susceptibility to RGC damage in degenerative disorders such as glaucoma. Also unlike the mouse or rat eye, the primate optic nerve head (ONH) has an elaborate collagenous lamina cribosa spanning the scleral canal, which is thought to be the primary site of RGC injury in glaucoma. Thus, novel approaches to cellular replacement need to account for these differences to better model the environment in the human retina and ONH. The macaque monkey non-human primate (NHP) glaucoma model results in highly reproducible damage to RGC axons and subsequent RGC loss. As such, the opportunity exists to further develop this system as a novel and powerful model to explore RGC replacement, including strategies that take into consideration the diversity of RGC subtypes. Human pluripotent stem cells (hPSCs) represent a virtually unlimited source of cells for the generation of RGCs for replacement purposes, with the recent demonstration of a variety of RGC subtypes derived from hPSCs. As such, the development of hPSC-based RGC cell replacement strategies can be customized to target those RGC subtypes preferentially affected by the degenerative process, resulting in a more robust engraftment of transplanted cells with greater axonal outgrowth and connectivity, with the goal of effectively restoring visual function.